In 1978, it was reported for the first time that an antisense molecule inhibited influenza virus infection. Since then, reports have been issued that antisense molecules inhibited the expression of oncogenes and HIV infection. In recent years, antisense oligonucleotides have become one of the most promising pharmaceuticals, because they specifically control the expression of undesirable genes.
The antisense method is based on the idea of controlling a unidirectional flow called the central dogma, i.e., DNA.fwdarw.RNA.fwdarw.protein, by use of an antisense oligonucleotide.
When a naturally occurring oligonucleotide was applied to this method as an antisense molecule, however, it was hydrolyzed with enzymes in vivo, or its permeation through the cell membrane was not high. To solve these problems, numerous nucleic acid derivatives have been synthesized, and studies thereon have been conducted. Examples of synthesized derivatives include a phosphorothioate having a sulfur atom substituting for an oxygen atom on the phosphorus atom, and a methylphosphonate having a substituting methyl group. Recently, molecules in which the phosphorus atom has also been substituted with a carbon atom, or in which the ribose has been converted to an acyclic skeleton have been synthesized (F. Eckstein et al., Biochem., 18, 592 (1979), P. S. Miller et al., Nucleic Acids Res., 11, 5189 (1983), P. Herdewijn et al., J. Chem. Soc. Perkin Trans. 1, 1567 (1993), and P. E. Nielsen et al., Science, 254, 1497 (1991)).
All of the resulting derivatives, however, have been unsatisfactory in terms of in vivo stability or ease of oligonucleotide synthesis.
Under the circumstances, there has been a demand for the provision of a nucleotide analog for an antisense molecule which readily permeates through the cell membrane in vivo, which is minimally hydrolyzed with an enzyme, and the synthesis of which is easy.